This invention concerns a method of drug discovery and resulting therapeutic agent for treating a patient with metastatic cancer in the liver stemming from a primary colorectal cancer or digestive tract disorder.
The inventor hereof has discovered that development of hepatic metastases is associated with an aberrant tissue-reconstitution process that results from bidirectional reciprocal effects between cancer cells and resident hepatic cells. On one hand, cancer cells and their soluble and exosomal proteins regulate gene expression in hepatic cells residing in, or infiltrating into, various sites of metastases. At these sites, cancer cells exert selective pressures on hepatic cells thereby shaping their functional phenotypes. Conversely, constituents of the liver microenvironment may also regulate gene expression in the cancer cells thereby controlling their fate and determining their ability to progress towards metastatic formation (for review, see Vidal-Vanaclocha, 2011a).
Additionally, there are pathophysiological processes such as aberrant hepatic regeneration, inflammation and fibrosis that change the hepatic microenvironment and notably affect development of metastases. Therefore, tumor microenvironment regulating hepatic metastasis in a given patient consists of structural and functional factors resulting from both hepatic-cancer cell interactions and previous or concurrent hepatic diseases (for review, see Vidal-Vanaclocha, 2011b).
Neoplasms from right and left colon and rectum frequently metastasize to the liver. At a transcriptional level, hepatic metastasis development is in part associated with marked changes in gene expression of colorectal cancer cells that may originate in a primary tumor. Other prometastatic changes occur in the liver and are regulated by hepatic cells, which represent a new microenvironment for metastatic colon cancer cells. In addition, hepatic parenchymal and non-parenchymal cell functions are also affected by both cancer cell-derived factors and various systemic pathophysiological factors of a patient having CRC.
Liver and gastrointestinal tract physiology and pathology are interrelating, For example, gallstones (cholelithiasis) and cholecystectomy are related to digestive system cancer through inflammation, altered bile flux, and changes in metabolic hormone levels. More importantly, it has been established that a statistically significant risk of colorectal cancer follows cholelithiasis (Lee et al, 2016; Gosavi et al, 2017). Similarly, fatty liver, which is a hepatic manifestation of metabolic syndrome, is a well-known risk factor for CRC (Barbois et al, 2017). If hepatic gene expression disorders precede CRC occurrence, early biomarkers of CRC risk and development may be assessed.
In the past two decades, a growing amount of data has been reported suggesting that carcinomas of the right and left colon should be considered as different tumor entities. Right-sided colon cancers (RCC) and left-sided colon cancers (LCC) are of different embryological origins, and various differences exist between them. Tumor location is associated with prognosis in colorectal cancer patients, and those with RCC have a significantly worse prognosis than those with LCC (Yahigi et al 2016). RCC should be treated distinctively from LCC (Zhao et al, 2017), and the establishment of standardized management for colon cancer by tumor location is needed.
Characterization of genes that are differentially expressed in tumorigenesis is an important step in identifying those that are intimately involved in the details of a cell's transformation from normal to cancerous, and from non-metastatic to metastatic cells, However, little is known about molecular changes that occur in key organs (as for example the liver) during the course of cancer development and its metastatic disease. While changes in the expression level of individual genes have been reported, investigation of gene expression changes that occur in the liver of patients with cancer and without cancer as provided by the present invention has not been previously known or documented.
In brief summary, there exists a need in the art for the identification of new CRC disease-associated hepatic genes as molecular biomarkers to, among other things, (i) monitor and assess the pathogenic contribution of liver to CRC and hepatic CRC metastasis development; (ii) identify and/or screen candidate cancer patients suitable for liver metastasis-specific therapies; and (iii) discover and/or screen pharmaceutical cellular and molecular compositions targeting those liver genes with CRC and CRC metastasis-stimulating activities in patients with and without colorectal cancer.
These and other needs are met by various aspects of the present invention.